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Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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December 15, 2010

Chiral What? Chiral How?

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Posted by Derek

Thanks to an email from a reader, I can bring you this very weird paper from Tetrahedron. The authors claim to have extracted a local plant and isolated nevirapine, (sold as Viramune by Boehringer Ingleheim as a reverse transcriptase inhibitor for HIV).
That's kind of odd. I'm no natural products expert, but I've sure seen a lot of them over the years, and that framework (and the N-cyclopropyl) don't look so likely to me. But hey, plants do odd things. That's not what's really puzzling about this paper. No, what's had me staring at it this morning is the claim that, in contrast to the marketed drug, this stuff is optically active nevirapine.

Say what? Try as I might, I can't see any plausible way that that's a chiral compound. The authors seem to think it is, though. They claim optical rotation, somehow, and then say that "The detailed structure and stereochemistry of compound 1 was established unambiguously by single crystal X-ray crystallography." But hold on - that's not as easy as it sounds. Getting absolute configurations from the X-ray data of light-atom-only molecules takes special efforts, and I don't see any being taken (molybdenum X-rays, direct methods, no talk of anomalous dispersion, etc.)

I'm just not willing to see that nitrogen atom as a source of chirality - if it were, shouldn't that be the focus of this whole paper? Instead, the authors just blithely tell us how neat it is that they've isolated the chiral material. In fact, they find it so neat that they tell us two times in a row:

This is a very interesting discovery that naturally occurring optically active nevirapine has been biosynthesized in the seeds of C.viscosa and the optically inactive nevirapine was designed as a selective non-nucleoside inhibitor of HIV-1 reverse transcriptase. It is also a remarkable ļ¬nding that the seed of C.viscosa is the source of optically active nevirapine, which was also designed and synthesized before its isolation from natural source.

This sounds like some sort of lunatic patent-busting exercise, to be honest. And it sounds as if someone doesn't know what a chiral compound is. And that whoever reviewed this for Tetrahedron was incompetent. And that the editor who let it through should be a least a little bit ashamed. Well?

Comments (73) + TrackBacks (0) | Category: Infectious Diseases | Natural Products | The Scientific Literature


1. jw on December 15, 2010 9:52 AM writes...

I dont really know what to say, Some nitrogens appear to be chiral as they prefer to be in one state over another, but I cant see even that being the case here

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2. capek on December 15, 2010 9:59 AM writes...

I'm looking at this as a possible anilide atropisomer. I'm still looking...

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3. Anonymous on December 15, 2010 10:11 AM writes...

any possiblity that the two pyridyl nitrogens are being coordinated by a metal ion?

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4. processchemist on December 15, 2010 10:23 AM writes...

I vote for the patent bursting attempt hypothesis. And this is not the first time that we see papers aimed in this direction.
Sales of Viramune are not disclosed by Boheringer, patent expires in 2012 but Cipla, Daiichi Sankyo's India and Ranbaxy have the generic already on the market. The usual mess, just another fancy asymmetry of the current system.

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5. petros on December 15, 2010 10:23 AM writes...


Atropisomerisem looks questionable but the reported rotaion (7.8 at 0.011) is pretty small.

And the mp is only 4 degrees different (lower) from that reported for nevaripine. Prehaps somone will check that the NMR is right

It's also a very odd natural product as you say.

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6. Stiv on December 15, 2010 10:24 AM writes...

it's weird that the cyclopropyl methylenes (and their associated carbons) have different shifts - should be free rotation around the C-N bond.

also, in Fig. 2 (the ORTEP-diagram), what is that thing behind molecule 1? ethyl acetate in the crystal?

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7. petros on December 15, 2010 10:31 AM writes...

Actually picking up on Stiv's poiint (#6). Would be regiosomer of nevaripine, with the methyl proximal to the cyclopropyl substituent be sufficient to give hindered rotation and chirality?

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8. Tex on December 15, 2010 10:53 AM writes...

Ok, we're all forgetting here that chirality and the ability to resolve enantiomers are two different things. If this molecule is not planar (as the X-ray indicates), then there are non-superimposable mirror images and therefore the molecule is chiral. However, if enantiomers can interconvert by a conformational exchange - it then depends on the barrier to inversion. In this case, I do not see immediately what would lead to a large barrier for interconversion. For molecules with chirality at trivalent nitrogen to be configurationally stable and thus resolvable (cf comment 1), this typically means being in a small ring (aziridines) or being bonded to oxygen (oxaziridines, N-alkoxyamines) in order to increase the N-inversion barriers.

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9. Industry Guy on December 15, 2010 10:54 AM writes...

Come on! The paper is from India....enough said. Add it to the pile of chemistry crap coming from there.

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10. Capek on December 15, 2010 10:58 AM writes...

Doesn't the space group of P-1 kind of give it away? It can't be stereochemically pure. With a z value of 2, the other molecule in the unit cell must be the mirror image.

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11. bgg on December 15, 2010 11:02 AM writes...

Perhaps the stabilizing forces involved in the crystal packing provide a sufficient barrier to inversion at N. Chiral crystals are known to form from achiral molecules.

But as for the paper, I don't really believe any of the conclusions.

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12. barry on December 15, 2010 11:15 AM writes...

The central ring would be anti-aromatic (4n) if it were planar. That seems to present the barrier to interconversion between one buckled form and the other. If so, that makes it one of the odd cases where chirality isn't atom-centered, but it wouldn't be unique.

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13. p on December 15, 2010 11:17 AM writes...

I'm away from my work computer and office so don't have access to the paper itself. But this should be simple: they claim to have isolated a known compound. They should have both an exact match for the NMR spectra and LCs that are clean and match by co-injection. They could then do a chiral LC and show that only one enantiomer is in the natural product while two are in the synthetic material.

Do they have any of these things or do they simply report a rotation?

The thing I always worry about with rotations from natural sources is how pure the stuff is. Get a little bit of another material that gives a big rotation in your sample and your numbers go out the window.

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14. Hap on December 15, 2010 11:17 AM writes...

The amide looks awfully hindered, but being that it can move the proton either with base or by tautomerism (acid), and thus relieve the rotational hindrance around the amide axis, I don't know how stable any stereo there would be.

I don't need to discard the paper because the authors are Indian - bad stereo and insufficient evidence for their conclusions is enough. I vote "pathetic patent-busting exercise", if that matters.

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15. barry on December 15, 2010 11:21 AM writes...

But the NMR (in the absence of a chiral-shift reagent) should be identical to that of racemic material, and the non-equivalence of the cyclopropyl methylene hydrogens should therefore have been analysed long ago.
It's still an improbable-looking natural product.

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16. @Industry Guy on December 15, 2010 11:23 AM writes...

Dude...clicking once on "Post" is enough. Also, lay off the Indians...there's enough garbage research from the US and EU being printed in higher-impact journals than Tetrahedron!

Long shot: Excluding the carbonyl, I count 16 pi-electrons within the ring skeleton. Could the compound be twisted at the amide to avoid Huckel antiaromaticity? Sorry, I don't have access to the paper or SI?

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17. BoredChemist on December 15, 2010 11:28 AM writes...

Maybe their polarimetry cell was contaminated with garam masala ;-)

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18. petros on December 15, 2010 11:38 AM writes...

There is no mention of cochromatography with the marketed drug